Epidermal cancer stem (ECS) cells are important potential targets of dietary cancer prevention agents. We have developed in vitro and in vivo cultivation systems that allow propagation of human ECS cells from squamous cell carcinoma. Using this system, we show that ECS cells display markedly enhanced sensitivity to treatment with dietary cancer prevention agent, sulforaphane (SFN), as compared to non-stem cancer cells. We propose that ECS cell subpopulation of tumor cells is selectively targeted by sulforaphane. We further show that expression of the polycomb group (PcG) stem cell maintenance protein, Ezh2, is markedly elevated in the ECS cell population and that SFN treatment suppresses the level of this regulator. We hypothesize that ECS cells are ultra-sensitive to SFN, compared to non-stem cancer cells, and that SFN reduces Ezh2 protein level and function thereby altering downstream target gene expression to reduce ECS cell survival. We further hypothesize that Ezh2 controls tumor cell production of angiogenic factors that drive tumor vascularization to permit rapid tumor expansion, and that SFN inhibits this. However, we do not have a good understanding of this regulation. First, what is the role of Ezh2 as a mediator of enhanced stem cell sensitivity to SFN and is suppression of Ezh2 protein function required for SFN-dependent suppression of cancer stem cell survival? Second, we do not know if ECS cells will display a similar enhanced SFN sensitivity in vivo and so it will be important to test. Third, we do not know the mechanism whereby Ezh2 and SFN influence tumor cell production of angiogenic agents to drive endothelial cell-dependent tumor vascularization. Our goal is to characterize the sulforaphane anti-stem cell mechanism of action with an ultimate goal of developing sulforaphane as an epidermal stem cell-directed cancer prevention agent.